Proteomic analysis of age‐dependent changes in protein solubility identifies genes that modulate lifespan

Abstract

While it is generally recognized that misfolding of specific proteins can cause late-onset disease, the contribution of protein aggregation to the normal aging process is less well understood. To address this issue, a mass spectrometry-based proteomic analysis was performed to identify proteins that adopt sodium dodecyl sulfate (SDS)-insoluble conformations during aging in Caenorhabditis elegans. SDS-insoluble proteins extracted from young and aged C. elegans were chemically labeled by isobaric tagging for relative and absolute quantification (iTRAQ) and identified by liquid chromatography and mass spectrometry. Two hundred and three proteins were identified as being significantly enriched in an SDS-insoluble fraction in aged nematodes and were largely absent from a similar protein fraction in young nematodes. The SDS-insoluble fraction in aged animals contains a diverse range of proteins including a large number of ribosomal proteins. Gene ontology analysis revealed highly significant enrichments for energy production and translation functions. Expression of genes encoding insoluble proteins observed in aged nematodes was knocked down using RNAi, and effects on lifespan were measured. 41% of genes tested were shown to extend lifespan after RNAi treatment, compared with 18% in a control group of genes. These data indicate that genes encoding proteins that become insoluble with age are enriched for modifiers of lifespan. This demonstrates that proteomic approaches can be used to identify genes that modify lifespan. Finally, these observations indicate that the accumulation of insoluble proteins with diverse functions may be a general feature of aging.

A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

“…A number of studies have reported biophysical features, environmental conditions, and molecular partners that promote or repress the initial aggregation of specific proteins (1,3,7,(13)(14)(15). More recently, it has been recognized that the regulation of many other proteins is disrupted as a consequence of these initial aggregation events (8,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). In a complementary approach, the origins of AD have been studied by analyzing Comparison between down-regulated and metastable biochemical pathways and networks.…”

“…Thus, protein aggregation is emerging as a widespread biological phenomenon, in which hundreds of different proteins can aggregate in aging, stress, or disease (9,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). To understand why some proteins aggregate whereas others remain soluble, we recently observed that many proteins in the proteome are insufficiently soluble relative to their expression levels (24).…”

Proteostasis and longevity: when does aging really begin?

“…Protein aggregation is associated with many age-related disorders, and increased protein oxidation, mislocalization, and aggregation are observed in aged organisms [2][3][4][5][6][7]. Intuitively, these findings can be explained by a gradual decline in protein biosynthetic and quality control pathways and a progressive accumulation of protein damage.…”

“…Despite this, why organisms age remains a complex mystery that if understood could have profound implications for the quality of human health. While the physiological decline associated with old age is easily recognizable, the mechanisms that determine aging are poorly understood; however, widescale loss of protein homeostasis (proteostasis) is proposed to be one of the "primary hallmarks of aging" [1].Protein aggregation is associated with many age-related disorders, and increased protein oxidation, mislocalization, and aggregation are observed in aged organisms [2][3][4][5][6][7]. Intuitively, these findings can be explained by a gradual decline in protein biosynthetic and quality control pathways and a progressive accumulation of protein damage.…”

More stressed out with age? Check your RNA granule aggregation

“…Notably, we and others have shown that several hundred proteins are highly prone to aggregate during normal aging in different model organisms. [15][16][17][18][19] In our recent study, 20 the proteomic analysis of the aggregating proteome from longlived C. elegans with reduced daf-2/insulin/IGF-1 receptor signaling highlighted a specific group of proteins namely RNA granule components. In particular we identified several stress granule components as well as 4 RBPs with LC prion-like domains thatbecamehighlyinsolublewithageincontrolanimals but not in long-lived animals.…”